School of Medicine, Meharry Medical College, Nashville, TN; Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN.
Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN.
Surgery. 2022 Jan;171(1):111-118. doi: 10.1016/j.surg.2021.04.045. Epub 2021 Jul 11.
BACKGROUND: Immunotherapeutic response failure of adrenocortical carcinomas highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell infiltration and improved outcomes in patients with adrenocortical carcinomas. We further dissect the role of mast cells in the tumor microenvironment of adrenocortical carcinomas by examining the tumor mast cell expression signatures and mast cell activity within the tumor microenvironment to provide additional insight into potential novel immunotherapeutic targets. METHODS: Using the CIBERSORTx computational immunogenomic deconvolution algorithm to analyze adrenocortical carcinoma tumor gene messenger RNA expression data (The Cancer Genome Atlas, N = 79), we estimated the abundance of tumor immune infiltrating mast cells and assessed prognostic potential of mast cell signaling genes as pro or antitumor signatures, as well as examined the impact on overall and disease-free survival. RESULTS: We stratified mast cell signaling genes with survival prognostic values (overall survival, disease-free survival, P < .05) into antitumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and protumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Antitumor mast cell signature, as the predominant phenotype, was associated with improved overall and disease-free survival. CONCLUSION: The deconvolution analysis of The Cancer Genome Atlas data identified mast cell infiltration in the adrenocortical carcinoma microenvironment as predominantly associated with antitumor activity. Future studies stemming from our findings may help define the role of mast cells in the tumor microenvironment and the impact on patient survival in patients with adrenocortical carcinomas. Modulation of tumor mast cell infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with adrenocortical carcinomas.
背景：肾上腺皮质癌的免疫治疗反应失败突出表明需要针对肿瘤微环境中的免疫细胞群体制定新策略，以克服肿瘤耐药性并增强治疗反应。最近的一项研究探讨了肿瘤肥大细胞浸润与肾上腺皮质癌患者改善预后之间的新联系。我们通过检查肿瘤微环境中的肿瘤肥大细胞表达特征和肥大细胞活性，进一步剖析肥大细胞在肾上腺皮质癌肿瘤微环境中的作用，为潜在的新型免疫治疗靶点提供更多的见解。
方法：使用 CIBERSORTx 计算免疫基因组去卷积算法分析肾上腺皮质癌肿瘤基因信使 RNA 表达数据（癌症基因组图谱，N=79），我们估计肿瘤免疫浸润肥大细胞的丰度，并评估肥大细胞信号基因作为促肿瘤或抗肿瘤标志物的预后潜力，以及检查其对总生存期和无病生存期的影响。
结果：我们将具有生存预后价值（总生存期、无病生存期，P<.05）的肥大细胞信号基因分层为抗肿瘤（ALOX5、CCL2、CCL5、CXCL10、HDC、IL16、TNF、TPSAB1、VEGFD）和促肿瘤（CXCL1、CXCL3、CXCL8、IL4、IL13、PTGS3、TNSF4、VEGFD）组。作为主要表型的抗肿瘤肥大细胞特征与改善的总生存期和无病生存期相关。
结论：癌症基因组图谱数据的去卷积分析鉴定出肾上腺皮质癌微环境中的肥大细胞浸润主要与抗肿瘤活性相关。我们的研究结果可能有助于定义肥大细胞在肿瘤微环境中的作用及其对肾上腺皮质癌患者生存的影响。肿瘤肥大细胞浸润的调节可能成为治疗肾上腺皮质癌患者和改善其生存的新型协同免疫疗法的潜在靶点。
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